Sodium valproate is an anti-epileptic medicament widely sold at the current time, in particular in the form of tablets assaying 500 mg per administration unit.
These tablets, which are provided with an enteric or programmed-release coating, are for this reason fairly large.
In consequence, such tablets will generally be disadvantageous, in particular for children or people experiencing difficulties in swallowing, for example elderly people.
For this type of patient, it thus appears desirable to have available administration forms which are better suited to their state or to their condition.
Moreover, sodium valproate has a rather unpleasant, bitter taste. It will consequently prove to be necessary to take into account this disadvantage in administration forms suitable for children, for example syrup forms or solutions to be taken orally, by masking this taste using various expedients.
However, administration forms such as syrups do not allow children to benefit from the advantages resulting in some cases from the gastroresistance and the prolonged release of the active ingredient.
Moreover, the adjustment of the dose of active ingredient to the weight of the child, the child posology per kg of body weight being observed, represents an additional constraint in paediatrics.
A few years ago, a new pharmaceutical dosage presentation appeared which makes it possible to satisfy some of these requirements. It consists of a fine semolina composed of microspheres, in which microspheres the active ingredient is most often covered with an isolating film. This fine semolina, sprinkled over a spoonful of semi-solid food, for example purée, compote or yoghurt, is administered as is.
However, the so-called microsphere pharmaceutical form lends itself poorly to sustained release of the active ingredient. This is because, for equal masses, the surface area developed by these spheres will increase as their diameter becomes smaller, the consequence of which will be that these microspheres dissolve faster.
In order to overcome this disadvantage, it will generally be recommended to provide these spheres with an appropriate coating which makes possible the desired delayed release.
While it is industrially possible to coat pharmaceutical microspheres, it is however lengthy because it requires a large amount of polymer to be deposited.
Various methods for manufacturing these microspheres, sometimes known as “prills”, are known and have been experimented with for various active ingredients.
One of them, applied to valproic acid, has been described in “Drug Development and Industrial Pharmacy”, 21(7), pp. 793-807 (1995).
According to this process, a mixture composed of white beeswax in the molten form, valproic acid and a surface-active agent is stirred in an aqueous medium at pH=4.5 while maintaining the mixture at a temperature greater than the melting temperature of the wax. On cooling, the spherical particles formed by dispersion solidify as microspheres.
However, the mean concentration of valproic acid in these microspheres does not exceed 17%, these microspheres having a certain concentration of the surfactant used, namely a mixture of ethoxylated or non-ethoxylated polysorbates.
Another technique for forming pharmaceutical microspheres resorts to the prilling technique.
According to this technique, described in particular in Pat. DE 2,725,924, an excipient, the melting point of which is less than 120° C., is melted, the dissolved or dispersed active ingredient can be added thereto and then this molten dispersion is passed through a vibrating nozzle which causes the jet to break up and spherical droplets to form, which cool as microspheres in falling.
This process has been applied, for example, to pharmaceutical ingredients with an undefined crystallization point which melt in the excipient, as described in patent EP 438,350. This excipient can be, for example, a fatty alcohol, such as stearyl alcohol, a fatty acid, such as stearic acid, a glycerol ester, a hydrogenated oil, a fatty acid salt, a polyol, a wax, a polyoxyethylene glycol or an esterified polyoxyethylene. Moreover, stearic acid is exemplified therein as excipient.
However, it was specified therein that, in the specific case of ketoprofen, fatty acids and their salts, glycerol esters, hydrogenated oils, waxes or esterified polyoxyethylenes alone can be used.
Other pharmaceutical ingredients have also been experimented with in the prilling technique.
Thus, tests on the manufacture of microspheres containing theophylline as active ingredient have been reported in the “Technical Bulletin”, No. 83, pp 3347 (1990) of the company Gattefossé, use being made, as matrix excipient, of combinations such as stearic acid/white wax or carnauba wax/glyceryl stearate (Precirol® WL 2155), optionally with addition of saturated polyglycolysed glyceride (Gelucire® 50-13), while taking into account the characteristics of these excipients with the process chosen.
However, problems of homogeneity were recorded which resulted, according to this publication, in so-called wax mixtures being abandoned for the formation of theophylline microspheres.
In the context of the present invention, attempts were made to apply this technique to sodium valproate. However, the first tests carried out, starting with a matrix comprising a stearic derivative, demonstrated a number of problems, including crystallization of the sodium valproate in the mixture subjected to prilling and a viscosity unsuitable for the manufacture of microspheres.
These disadvantages were displayed in particular during the use of a 68/2/30 by weight mixture of stearyl alcohol/Gelucire® 50-13/sodium valproate.
Moreover, tests making use of sodium valproate and stearic acid as excipient showed a high degree of incompatibility, since precipitation brought about by contact of these ingredients is recorded.
It consequently appears illusory to transpose to sodium valproate the matrix excipients commonly used in the prior art for the preparation of pharmaceutical microspheres by the prilling technique.
In addition, the fruitless tests reported, on the one hand, in the state of the art and, on the other hand, in the context of the present invention convincingly show that there does not exist a standard excipient which can be employed in a prilling process whatever the active pharmaceutical ingredient used.
Consequently, the development of an administration form for sodium valproate which is simultaneously easy to use in paediatrics and geriatrics, capable of masking the unpleasant taste of this active ingredient and preferentially possesses a sustained-release profile remains of undeniable interest.